Chemistry and Biochemistry of HCA.pdf - AFBoard.com

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Reviews J. Agric. Food Chem., Vol. 50, No. 1, 2002 15 reduced significantly by the chronic administration of (-)-HCA (104). Chee et al. (105) have observed species-specific response to (-)-HCA. Acute administration of (-)-HCA caused the depression of in vivo rates of fatty acid synthesis in the livers of chickens and rats. Chickens appeared to be more sensitive to the inhibitory effects of (-)-HCA than did the rats. Oral administration of (-)-HCA significantly reduced the rate of in vivo hepatic fatty acids and cholesterol synthesis, and there was a reduction in serum triglyceride and cholesterol levels in normolipidemic rats. It was also observed that (-)-HCA significantly reduced the hypertriglyceridemia and hyperlipogenesis in genetically obese Zucker rats, fructose-treated rats with elevated triglyceride, and Triton-treated rats (92, 106). Young Zucker lean (Fa/-) and obese (fa/fa) female rats were fed with (-)-HCA, and decreases in body weight, food intake, percent of body fat, and fat cell size in the lean rats were observed (107). In the obese rats food intake and body weight were reduced, but the percent of body fat remained unchanged and maintained a fat cell size equivalent to that of their obese controls. This study indicates that the obese rats, despite a substantial reduction in body weight produced by (-)-HCA, still defend their obese body composition. Rao and Sakariah (108) observed that inclusion of (-)-HCA in the lipogenic diet resulted in significant reduction in food intake, body weight, epididymal fat, and serum triglyceride in the albino rats and also a decrease in the feed efficiency ratio. The decreases in food intake, body-weight gain, and feed efficiency ratio brought about by (-)-HCA were dependent on the content of this compound in the diet. The study encouraged exploration of the efficacy of (-)-HCA in the control of obesity and hypertriglyceridemia. Effect of ())-HCA on Ketogenesis. Brunengraber et al. (95) reported that ketogenesis by livers of fed rats perfused without free fatty acid is strongly inhibited by (-)-HCA. It seems that such ketogenesis occurs via an extramitochondrial pathway that depends on the citrate cleavage reaction for its supply of extramitochondrial acetyl-CoA, which operates in carbohydratefed animals (109). However, the same parameter was not inhibited by (-)-HCA when livers from starved rats were perfused with oleate. On the other hand, the ketogenesis increased somewhat by (-)-HCA when livers from fed rats were perfused with oleate. The intramitochondrial pathway predominates either in starved animals or when the concentration of fatty acid is high or both. In the case of the rumen epithelium of sheep, the absence of any significant cytoplasmic component was emphasized by (-)-HCA, which should inhibit ketogenesis if ATP:citrate lyase plays any function in the process (110), but there was no such inhibition, lending support to the theory that ketogenesis proceeds exclusively through the mitochondrial pathway. Other Biological Effects of ())-HCA. (-)-HCA did not affect the rate of oxygen consumption by rat brain synaptosomes, and the activities of fatty acid synthase, carnitine acetyltransferase, glucose 6-phosphate-dehydrogenase, and acetyl-CoA synthetase but inhibited the activities of isocitrate dehydrogenase, malate dehydrogenase (decarboxylating), and aconitate hydratase at millimolar concentrations (50). (-)-HCA blocked dexamethasone stimulation of cytidylyltransferase but not of fatty acid synthase in lung tissue (111). Brunengraber et al. (95) observed that in rat liver, the inhibition of fatty acid synthesis by (-)-HCA was associated with an increase in the tissue content of glucose 6-phosphate and fructose 6-phosphate and a diminution in glycolytic intermediates from fructosebisphosphate to phosphoenol pyruvate. Presumably, the citrate content is elevated in cytoplasm in the presence of (-)-HCA. This can be expected to result in a reduced activity of phosphofructokinase because citrate is wellknown to act as an inhibitor of this enzyme (112-114). It has also been seen that AMP contents drop in the presence of (-)- HCA. This can also be expected to reduce the activity of phosphofructokinase, because AMP is an activator of this enzyme (115). The inhibition of phosphofructokinase by (-)- HCA in rat hepatocytes has also been reported by McCune et al. (116). It can be concluded that in rat liver, the inhibition of phosphofructokinase by (-)-HCA leads to the accumulation of glucose 6-phosphate and fructose 6-phosphate and the decrease of glycolytic intermediates beyond fructosebisphosphate as the reaction catalyzed by phosphofructokinase in glycolysis is irreversible and controls the glycolysis. Chronic metabolic acidosis increases proximal tubular citrate uptake, causing hypocitraturia associated with an increase in cortical ATP:citrate lyase activity and protein abundance. Hypokalemia, which causes only intracellular acidosis, also caused hypocitraturia and increased renal cortical ATP:citrate lyase activity. Inhibition of this enzyme with (-)-HCA significantly abated hypocitraturia and increased urinary citrate excretion in chronic metabolic acidosis and in K + depletion (117). These results suggest an important role of ATP:citrate lyase in proximal tubular citrate metabolism. (-)-HCA has been reported to alter the pyruvate metabolism by tumorigenic cells (118). Pyruvate consumption by tumor cells declined, but the mean percentage of oxidation increased with (-)-HCA. Possible Mode of Action on Reduction in Food Intake. The chronic oral administration of (-)-HCA to growing rats caused a reduction in body-weight gain, food consumption, and total body lipids. However, administration of equimolar amounts of citrate did not alter weight gain, appetite, or body lipids, and there was no increase in liver size or liver lipid content with either treatment. Paired feeding studies demonstrated that the reduction in food intake accounted for the decrease in weight gain and body lipid observed with (-)-HCA treatment, and this decrease in calorie intake was not responsible for the druginduced depression of hepatic lipogenesis (66, 67). Rao and Sakariah (108), in their studies, suggested that the reduction in appetite in (-)-HCA-fed rats seems to be a specific effect of (-)-HCA ingestion and not due to alterations of taste as the diet fed to control group contained citrate at a level equivalent to that of (-)-HCA in the experimental diet. In view of the close structural relationship of (-)-HCA to citrate, it is reasonable to believe that (-)-HCA does not affect the taste of the food. Panksepp et al. (119) evaluated the capacity of various salts of (-)-HCA to produce conditioned rejection of a 0.25% saccharin solution and concluded that the food intake was reduced by (-)-HCA only during the first hour following administration of the drug and the magnitude of appetite rejection did not correspond to the degree of conditioned rejection, lending support to the conclusion that the food intake reduction was not merely a consequence of aversive effects of the drug. A number of complex factors have been implicated in the appetite regulation and feeding behavior (67). Glucose utilization rates (120), unidentified humoral factor(s) in blood from satiated rats (121), enterogastrone (122) and other gastrointestinal hormones, plasma and brain tryptophan, brain serotonin interrelationships (123-127), and brain catecholamines (128) have all been suggested to play their role in the regulation of feeding behavior. Because (-)-HCA was demonstrated to inhibit fatty acid and cholesterol synthesis, presumably through a reduction
16 J. Agric. Food Chem., Vol. 50, No. 1, 2002 Reviews in acetyl-CoA pool in lipogenic tissues (65), the same effect would be expected in any cell possessing ATP:citrate lyase. Ricny and Tucek (129) have observed that the availability of acetyl-CoA had a decisive influence on both the rate of synthesis of acetylcholine and its steady-state concentration with glucose as the metabolic substrate in rat brain slices. Acetylcholine released by the phrenic nerve was measured in the isolated perfused rat hemidiaphragm; when (-)-HCA was added to the perfusate, the release of acetylcholine was stabilized at a level 40% below the control value (130). (-)-HCA was reported to inhibit the synthesis of acetylcholine in rat brain slices (90, 131, 132). These results suggested that citrate transport and subsequent cleavage give rise to acetyl-CoA as the principal precursor of acetylcholine synthesis. Sterling et al. (133) reported that in rat brain cortex, (-)-HCA reduced the incorporation of [ 3 H]- glucose and [ 14 C]-β-hydroxybutyrate to the acetyl moiety of acetylcholine. They suggested that in adult rats, β-hydroxybutyrate could contribute to the acetyl moiety of acetylcholine, possibly via the citrate cleavage pathway. Ricny and Tucek (134) observed the effects of (-)-HCA on the concentration of acetyl- CoA and acetylcholine in the tissue and on the release of acetylcholine into the media were investigated in experiments on slices of rat caudate nuclei incubated in different media. With glucose as the main metabolic substrate, (-)-HCA diminished the concentration of acetyl-CoA in all of the media used. ATP: citrate lyase appears to provide about one-third of acetyl-CoA used for the synthesis of acetylcholine. Gibson and Peterson (135) have shown that the (-)-HCA-reduced incorporation of [U- 14 C]glucose into acetylcholine was greater in septal than in hippocampal slices, indicating that acetylcholine metabolism varies regionally. Recently, Szutowicz et al. (136) reported that in Ca 2+ -activated rat synaptosomes, both synaptosomic acetyl- CoA and acetylcholine syntheses were suppressed by 27 and 29%, respectively, by 1 mM (-)-HCA. The impairment of acetylcholine synthesis with (-)-HCA was also reported in the brain stem of neonatal rat (137). All of these in vitro studies revealed that (-)-HCA can depress acetylcholine synthesis in nerve tissues, although so far there is no evidence of reduced synthesis of acetylcholine in intact animals with the administration of (-)-HCA. Sullivan et al. (67) suggested that if (-)- HCA could penetrate the blood-brain barrier, then the depression of acetylcholine levels or rate of turnover in the brain resulting from a decreased precursor pool could affect cholinergic receptor systems that might be involved in feeding behavior. Fatty acid synthesis regulates fatty acid oxidation by a wellcharacterized mechanism (138, 139). In this paradigm, malonyl- CoA levels rise during fatty acid synthesis and result in inhibition of carnitine palmitoyl transferase 1 (CPT 1) mediated uptake of fatty acids into the mitochondria. This results in elevation of cytoplasmic long-chain fatty acyl (LCFA)-CoAs and diacylglycerol molecules that may play a role in signaling, which leads to the proposal that malonyl-CoA levels act as a signal of the availability of physiological fuels (140). One such proposal for maolnyl-CoA is the mediation of nutrient-stimulated secretion in the beta cells. Glucose-sensing neurons, which regulate feeding in the hypothalamus, share many features with the beta cells, including expression of glucokinase and the adenosine-sensitive potassium channel (141). The studies of Chen et al. (142) showed that (-)-HCA profoundly inhibited the glucose-stimulated insulin secretion (GSIS) from beta cells and also provided evidence for the pivotal role of malonyl-CoA suppression of CPT 1 with attending elevation of the cytosolic LCFA-CoA concentration in GSIS from the normal pancreatic beta cell. Moreover, Saha et al. (103) reported that inhibition of ATP:citrate lyase by (-)-HCA markedly diminished the malonyl-CoA level, indicating that citrate was the major substrate for the malonyl-CoA precursor, that is, cytosolic acetyl- CoA, and also there is sufficient evidence that (-)-HCA inhibits ATP:citrate lyase (47-51), limiting the pool of cytosolic acetyl- CoA, the precursor of malonyl-CoA. This type of regulation of malonyl-CoA level may affect the signaling of fuel status in hypothalamic neurons regulating feeding behavior, lending support that (-)-HCA may represent a biochemical target for the control of appetite/feeding behavior and body weight. Thus, (-)-HCA seems to act at the metabolic level and not directly at the central nervous system as classical appetite depressants do. ())-HCA May Promote Glycogenesis, Gluconeogenesis, and Lipid Oxidation. The inhibition of ATP:citrate lyase by (-)-HCA causes less dietary carbohydrate to be utilized for the synthesis of fatty acids, resulting in more glycogen storage in the liver and muscles. Sullivan et al. (143) reported an increase in the rate of in vivo hepatic glycogen synthesis with the administration of (-)-HCA. Sullivan et al. (144) and Sullivan and Green (145) proposed that (-)-HCA acted primarily through its effects on the appetite, possibly involving increases in glycogen levels. Even though the administration of (-)-HCA increased the hepatic glycogen contents in rats, Hellerstein and Xie (146) demonstrated that neither hepatic glycogen nor the hexosephosphates are involved in the food-intake suppressive effects of (-)-HCA. It seems the increased hepatic fatty acid oxidation leading to increased levels of acetyl-CoA and ATP plays some role in this effect. In a well-fed state, the hepatic carnitine levels are far too low to activate CPT 1. The rate-limiting enzyme for hepatic lipid oxidation, CPT 1, is activated by exogenous carnitine and inhibited by malonyl-CoA. The lipogenesis inhibitor (-)-HCA can decrease the production of malonyl-CoA in hepatocytes by potent inhibition of ATP:citrate lyase and may activate CPT 1, which can facilitate lipid oxidation. Earlier studies demonstrated that (-)-HCA can reduce body-weight and fat accumulation in growing rats, owing to the reduction in appetite. From the above views McCarty (147) hypothesized that joint administration of (-)-HCA and carnitine should therefore promote hepatic lipid oxidation, gluconeogenesis, and satiety. In a recent study, joint administration of pyruvate, (-)-HCA, and carnitine to obese subjects was associated with a remarkable rate of body-fat loss and thermogenesis, strongly suggestive of uncoupled fatty acid oxidation (148). The reduction of free fatty acids by stimulating hepatic oxidation with (-)-HCA and carnitine may ameliorate risk factors associated with abdominal obesity (149). Sustained aerobic exercise requires a severalfold increase in hepatic glucose output. An increasing proportion of this elevated glucose output must be provided by gluconeogenesis. Thus, preadministration of (-)-HCA may aid endurance during postabsorptive aerobic exercise by promoting gluconeogenesis. Carnitine and bioactive chromium may potentiate this benefit. The utility of this technique may be greatest in exercise regimens designed to promote weight loss (150). The ability of exercise to selectively promote fat oxidation should be optimized if exercise is done postabsorptively (preferably during morning fasting metabolism), if (-)-HCA and carnitine are administered prior to exercise, if the exercise regimen is of moderate intensity and prolonged duration, and if no calories are ingested for several hours following exercise (151). Kriketos et al. (152) did not detect any effect of (-)-HCA administration on lipid oxidation, respiratory quotient (RQ), and
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